6beta-methyl-5alpha-androst-2-en-17-one and derivatives thereof



United States Patent 3,387,007 6B-METHYL-5a-ANDROST-Z-EN-fl-ONE ANDDERIVATIVES THEREOF Raymond E. Counsell, Ann Arbor, Mich, and Paul D.Klimstra, Northbrook, Ill., assiguors to G. D. Searle &

(30., Chicago, 11]., a corporation of Delaware No Drawing. Filed Mar. 8,1966, Ser. No. 532,556 9 Claims. (Cl. 260-3975) ABSTRACT OF THEDISCLOSURE 6,8 methyl a androst-2-en-17-one and derivatives thereofuseful as hormonal agents as evidenced by their anabolic and androgenicproperties and useful also as inhibitors of dicotyledonous seedgermination.

The invention herein described pertains to novel steroidal derivativescharacterized by a 6,8-methyl substituent and by a doubly bonded linkagebetween carbon atoms 2 and 3. These substances are more particularlydefined as 6,B-methyl-Su-androst-Z-en-l7-one and related derivatives andare specifically represented by the following structural formula CH3 CH3'fj. ti)

wherein X is a carbonyl or radical of the formula wherein n is apositive integer less than 8. Specific examples of the lower alkylradicals defined by the formula C H are methyl, ethyl, isopropyl andbutyl, of the lower alkenyl radicals represented by C H are vinyl,propenyl and isobutenyl and of the lower alkynyl radicals 3,387,007Patented June 4, 1968 denoted by the formula C H are ethynyl, propynyland isopentynyl.

The compounds of the present invention are valuable pharmacologicalagents. They exhibit hormone-like activity, for example, as ismanifested by their anabolic and androgenic properties. They areparticularly suitable for that purpose by virtue of the absence ofundesirable estrogenie side-effects. These compounds are, furthermore,inhibitors of dicotyledenous seed germination.

A convenient process for manufacture of the novel compounds comprisingthe present invention involves the utilization of starting materialsrepresented by the following structural formula CH3 0 H3 i H i wherein Xhas the identical meaning hereinbefore disclosed. The 3-hydroxy group isconverted to a suitable ester function, and the resulting esters areheated at elevated temperature, preferably in an inert organic solventmedium, to afford the desired A compounds. Arylsulfonyl esters such asthe p-toluenesulfonate are particularly suitable for that purpose.3j8-hydroxy-6fi-methyl-5aandrostan-17-one is thus contacted at roomtemperature with p-toluenesulfonyl chloride in pyridine to yield thecorresponding 3-p-toluenesulfonate, and that ester is heated incollidine solution at the reflux temperature, thus producing6/3-methyl-5a-androst-2-en-l'7-one.

The l7-esterified compounds of the present invention are convenientlyproduced by acylation of the instant l7- hydroxy substance. Thatcompound, i.e. 6B-methyl-5aandrost-Z-en-IZB-ol, thus affords thecorresponding 17- acetate when contacted with acetic anhydride inpyridine and the corresponding 17-(2-cyclopentylpropionate) when2-cyclopentylpropionyl chloride is the acylating 0 agent.

Reaction of the instant 17-ketone with the appropriate organometallicreagent results in the 17-(lower aliphatic hydrocarbon) substitutedderivatives encompassed by the present invention. As a specific example,the addition of methyl magnesium bromide to that ketone results in 65,l7a-dimethyl-5ot-androst-2-en-l718-01. An additional example is thereaction with lithium acetylide to produce17a-ethynyl-6fi-methyl-Sa-androst-Z-en-17,8-01.

An alternate process available for manufacture of the instant 17-(l0weralkenyl) derivatives involves partial reduction of the correspondingl7-(lower alkynyl) compounds. That transformation is readilyaccomplished by catalytic hydrogenation in pyridine solution. Theaforementioned 17a-ethynyl-6B-methyl-5or-androst-2-en-175-01 is thusshaken with hydrogen and 5% palladium-on-carbon catalyst in pyridine toaiford 6;8-methyl-l7a-vinyl-5aandrost-2-en-l7fi-ol.

The invention is illustrated more fully by the examples which follow.These examples are given by way of illustration only, however, and arenot to be construed as limiting the invention either in spirit or inscope as many modifications both in materials and methods will beapparent from this disclosure to those skilled in the art. In thefollowing examples, temperatures are given in degrees centigrade C.) andquantities of materials in parts by weight unless otherwise noted.

Example 1 A mixture containing 10 parts of3,6-hydroxy-6fi-methyl-5wandrostan-17-one, parts of p-toluenesulfonylchloride and parts of pyridine is allowed to stand at room temperaturefor about 16 hours, then is poured carefully into a mixture of ice andwater. The precipitate which forms is collected by filtration, washed onthe filter with water and dried in air to yield3B-hydroxy-6fl-methyl-5aandrostan-l7-one 3-p-toluenesulfonate.

The latter crude ester is dissolved in 500 parts by volume of collidine,and the resulting reaction mixture is heated at the reflux temperaturefor about 6 hours, then is cooled and poured into a mixture containingice and excess 10% aqueous sulfuric acid. The resulting precipitate isisolated by filtration, then is washed on the filter with water. Furtherpurification is effected by extraction into ether, washing of the ethersolution with water, drying over anhydrous sodium sulfate containingdecolorizing carbon and removal of the solvent by distillation underreduced pressure. The initially oily residue solidifies upon standing,then is recrystallized from aqueous methanol to yield6fi-methyl-5a-androst-2-en-l7-one, melting at about 899l. This compoundis represented by the following structural formula 0 0113f w d; C113Example 2 To a solution of 3.5 parts of 6fl-methyl-5a-androst2-en-l7-one in 162 parts of tetrahydrofuran is added 9 parts of lithiumtri-(tertiary-butoxy) aluminum hydride, and the resulting mixture isstirred at room temperature for about 4 hours. At the end of that timethe reaction mixture is poured into an ice-10% aqueous acetic acidmixture, and the precipitate which separates is isolated by filtration,washed on the filter with water and dried in air. Further purificationof that product by recrystallization from methanol yields pure6fi-methyl-5e-androst-Z-enl7fl-ol, which displays a melting point atabout 117-120 and an optical rotation, in chloroform, of +l3.5.

Example 3 A mixture containing one part of 6B-methyl-5wandrost-2-en-l7/3-ol, 10 parts of acetic anhydride and 20 parts of pyridine iskept at room temperature for about 16 hours, then is poured into icecold water. The resulting aqueous mixture is cooled at 05, and theprecipitated product is collected by filtration, then washed with water.Purification of the resulting crude product by recrystallization frommethanol affords 6B-methyl-5u-androst-2-en-173-01 17-acetate, melting atabout 89-90 and exhibiting an optical rotation, in chloroform, of +l.5.

Example 4 When an equivalent quantity of propionic anhydride issubstituted in the procedure of Example 3, there is pro duced6fl-methyl-5et-androst-Z-en-l7fl-ol l7-propionate.

4 Example 5 To a solution of one part of GB-methyl-Sa-androst-2-enl7-onein 17.5 parts of ether is added 25 parts by volume of 3 M etherealmethyl magnesium bromide, and the resulting reaction mixture is heatedat the reflux temperature with stirring in an atmosphere of nitrogen forabout 24 hours. At the end of that reaction period, the mixture ispoured into saturated aqueous ammonium chloride containing ice, and thatmixture is made acidic by the addition of dilute hydrochloric acid. Thatacidic aqueous mixture is extracted with ether, and the ether layer isseparated, washed with Water, dried over anhydrous potassium carbonatecontaining decolorizing carbon and concentrated to dryness bydistillation under reduced pressure. The resulting glass-like residue isrecrystallized from aqueous methanol to yield6,8,l7wdimethyl-Sa-andmst-Z-en-175- ol, melting at about 86.5. Itexhibits an optical rotation, in chloroform, of 3.

Example 6 When an equivalent quantity of ethyl magnesium bromide issubstituted in the procedure of Example 5, there is obtainedl7a-ethyl-6B-rnethyl-5ot-androst-2-en-17fl-ol.

Example 7 To a solution of 2.5 parts of 6fl-methyl-5a-andrOst-Z-enl7-onein 67.5 parts of tetrahydrofuran is added 6.5 parts of the 30% lithiumacetylide70% ethylene diamine complex. Acetylene gas is then bubbledinto the mixture for approximately 4 hours, following which time thereaction mixture is stirred for about 48 hours. Saturated aqueousammonium chloride and Water are successively added, and the resultingmixture is extracted with benzene. The organic layer is separated,washed successively with dilute hydrochloric acid and dilute aqueoussodium bicarbonate, then dried over anhydrous sodium sulfate containingdecolorizing carbon. Removal of the solvent by distillation underreduced pressure results in a glass-like residue, which is purified bychromatography on silica gel followed by elution with 5% ethyl acetatein benzene. The eluted fraction is isolated and purified further byrecrystallization from aqueous methanol to yield l7wethynyl-6fl-methyl-5a-androst2-en-175-01, which displays a melting point atabout l30-133.

Example 8 When an equivalent quantity of lithium .l-propynylide issubstituted in the procedure of Example 7, there is produced6,8-methyl-d7a-propynyl-Su-andrOst-Z-en-17 8-01.

Example 9 A mixture containing one part of 17a-fiihYnYl-6,Bmethyl-5a-androst2-en173-01, 0.1 part of 5% palladiumon-carbon catalystand 50 parts of pyridine is shaken with hydrogen at atmospheric pressureand room temperature until one molecular equivalent of hydrogen isabsorbed. The catalyst is removed by filtration, and the filtrate isconcentrated to dryness under reduced pressure to yield 6fl-methyl17ot-vinyl-5a-androst-2-en 17,8-01.

Example 10' By substituting an equivalent quantity of 6/8-methyl-17oupropynyl-5a-androst-2-en-117/3-01 and otherwise proceeding accordingto the processes described in Example 9, there is produced6,B-methyl-17a-propenyl-5a-androst- 2-en-17/3-ol.

Example 11 To a solution of one part of Gfl-methyl-5a-'androst-2-en-l7fi-ol in 25 parts of pyridine is added dropwise, over a period of afew minutes, 2 parts by volume of 2-cyc1opentylpropionyl chloride, andthe resulting reaction mixture is stirred for about one hour. At the endof that time the reaction mixture is poured into a mixture of ice andwater, then is extracted with ether. The ether layer is separated,washed successively with dilute hywherein Y is hydrogen or a radicalrepresented by the formulas H C(lower alkyl) H C -C(lower alkylene) l mbeing a positive integer less than 3, and Z is hydrogen or a radicalrepresented by the formulas wherein n is a positive integer less than 8.

2. As in claim 1, a compound of the formula and and

OH CH 3. As in claim 1, a compound of the formula i (lower alkenyl) 4.As in claim 1, a compound of the formula j (lower alkynyl) 5. As inclaim 1, a compound of the formula 0 C 0 (lower alkyl CH 6. As in claim1, the compound which is 613,17or-dimethyI Sa-androst-2-en-l-7fl-ol.

7. As in claim 1, the compound which is GB-methyl- Su-HIIdIOSt-2-6I117/3-O1.

8. As in claim 1, the compound which is 6 3-methyl- 5a-androst-2-en17/3-ol 17-acetate.

9. As in claim 1, the compound which is17a-ethynylpl-methyl-5a-an-drost-2-en473-01.

References Cited UNITED STATES PATENTS t1 1/:1966 Wechter et a1260239.55

8/ 1965 Counsell et a1.

OTHER REFERENCES Velarde et al., J. Org. Chem. 24, pp. 311-313 (-1959).

LEWIS GO'I'IS, Primary Examiner. T. M. M'ESHB'ESHER, Assistant Examiner.

